Herceptin® 150r powder for infusio Trastuzumab

150 mg

For intravenous V EXP

Batch

Roche

With patent protection on Genentech’s blockbuster drug trastuzumab (Herceptin) set to expire in the United States in 2019, several companies, including Mylan Pharmaceuticals, are developing their own versions of the biologic.

Amgen’s Neupogen (filgrastim), used to treat neutropenia.

In contrast to generic drugs, biosim- ilars are not exactly identical to their corresponding brand-name counter- parts. Whereas generic drugs are copies of small-molecule drugs with rela- tively simple chemical compositions, biosimilars correspond to complex large-molecule biologics and must be synthesized from living organisms.

Because biosimilars are impossible to precisely replicate, the FDA requires manufacturers to perform extensive analyses and conduct confirmatory clinical studies demonstrating that the products are highly similar to their branded counterparts, without any clinically meaningful differences.

“This is one of the first trials with biosimilars in oncology to demon- strate similar efficacy, safety, and immunogenicity against the reference product,” said Rugo. - Janet Colwell

Piecing Together the Adrenal Cancer Puzzle

Researchers from 39 institutions in six countries have joined forces to extensively characterize adrenocorti- cal carcinoma (ACC), a rare endocrine cancer that affects just two in every million people worldwide. ACC is often diagnosed at an advanced stage, so its 5-year survival rate ranges from 6% to 13%. Standard treatments for metastatic disease-chemotherapy, radiation, and the hormone-blocking agent mitotane-are palliative and have remained unchanged since the 1970s.

The analysis, part of The Cancer Genome Atlas, was led by Thomas Giordano, MD, PhD, and Gary Hammer,

MD, PhD, at the University of Michigan in Ann Arbor; and Roel Verhaak, PhD, at The University of Texas MD Anderson Cancer Center in Houston.

The team used several molecular plat- forms to scrutinize 91 tumors, includ- ing whole-exome and RNA sequencing, and DNA methylation profiling (Cancer Cell 2016;29:723-36). They found that 8% of the samples harbored inactivat- ing PRKAR1A mutations-”a new twist in the story,” Giordano says, given that alterations in this gene were thought to occur only in benign adrenal disease. They also observed loss of ZNRF3 in almost 20% of cases, resulting in consti- tutive activation of Wnt signaling.

“We knew Wnt signaling is impor- tant in adrenal cancer biology-some tumors have an initiating mutation in the ß-catenin gene [CTNNB1], which correlates with poor survival,” Hammer explains. “This discovery that ZNRF3 is a critical mediator adds another level of complexity to Wnt pathway activation.” Small-molecule inhibitors of Porcupine, an enzyme that processes Wnt ligands, are in phase I clinical trials for various cancers, he adds, and “we’re looking forward to testing their efficacy in ACCs lacking ZNRF3.”

Additionally, the researchers noted that a sizeable proportion of ACCs displayed evidence of profound genomic instability-often whole- genome doubling, which was associ- ated with more aggressive disease and decreased survival. Why this happens so frequently “is an open mechanistic question,” Giordano says.

By clustering their data, the research- ers pinpointed three ACC subtypes with different DNA methylation levels: low, intermediate, and high. Statistical analyses showed distinct clinical out- comes-the corresponding tumor recur- rence and/or metastasis rates were 7%, 56%, and 96%. The median progression- free survival was not reached in the first subtype; in the intermediate- and high- methylation subtypes, it was 38 months and 8 months, respectively.

“It looks like DNA methylation is a major driver [of the different sub- types],” Giordano observes, “so we’re looking to develop this signature into a full, analytically valid prognostic assay.” Currently, ACCs are classified as low- or high-grade based on mitotic activity under the microscope, “which

isn’t all that informative,” he adds. “A three-group classification would enable more confident treatment decisions.”

Ultimately, “we view our study as more of a hypothesis generator,” Hammer says, “and although it’s a long road ahead, I think we have the first steps to facilitating targeted therapy development for ACC.”

“There’s much to do, to better under- stand all our observations,” Giordano agrees, “but the fact that clinical out- come is linked means we’re at least bark- ing up the right tree.” -Alissa Poh

FDA Approves Drug Combo for Kidney Cancer

The FDA approved the combina- tion of lenvatinib (Lenvima; Eisai) and everolimus (Afinitor; Novartis) to treat advanced or metastatic renal cell carci- noma (RCC) in mid-May. The approval marks the first time that a tyrosine kinase inhibitor (TKI) and an mTOR inhibitor have been combined successfully as a second-line treatment for patients with RCC whose tumors advance despite previous VEGF-targeted treatment.

“We have been hoping to treat kidney cancer with this type of vertical blockade for some time, but previous combinations have been unsuccessful due to high toxicity,” says Ana Molina, MD, a medical oncologist at NewYork- Presbyterian Hospital and Weill Cor- nell Medicine in New York, NY.

Until recently, oncologists had two second-line treatment options: everoli- mus and the TKI axitinib (Inlyta; Pfizer). New approvals over the past few months have increased that number to five, including the new lenvatinib-everoli- mus combination; the PD-1 check- point inhibitor nivolumab (Opdivo; Bristol-Myers Squibb); and cabozantinib (Cabometyx; Exelixis), another TKI.

Together, lenvatinib and everolimus have a synergistic effect by blocking multiple points along the VEGF and mTOR signaling pathways that are criti- cal to tumor growth, says Molina. In addition, lenvatinib is a strong inhibitor of FGF receptors, which have been implicated as a potential mechanism of resistance to VEGF-targeted treatments.

The approval was based on a phase II trial in which 153 patients with advanced or metastatic RCC whose disease progressed within 9 months

AAGR

AAGR American Association for Cancer Research

CANCER DISCOVERY